Prayer of the Epileptologist

Transcription

1 Prayer of the Epileptologist Lord, grant that my work increase knowledge and help other men. Failing that, Lord, grant that it will not lead to man's destruction. Failing that, Lord, grant that my article in Epilepsia be published before the destruction takes place. Walker Percy

2 Epilepsy in Long Term Care Patients Old Concepts and New Data Amir Arain, M.D. Vanderbilt University

3 Long term care patients Patients with mental retardation and developmental disability Geriatric patients

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5 Seizures in Patients with MR/DD 1/5 th of the population of intellectually disabled have epilepsy Incidence greatly varies with epidemiological methods. In this population, there is a high incidence of confounding nonepileptic events Uncontrolled seizures effect the life of individuals and care takers alike regardless of intellectual disability

6 Epilepsy, Concomitant Cerebral Palsy, and Severity of MR In several studies epilepsy risk has been positively correlated with severity of MR Jacobson et al 1983: N= % had MR Epilepsy in 23% and CP in 16% Epilepsy in 9% of mild MR and 43% of severe MR CP in 9% of mild MR and 29% of severe MR

7 Types of Seizures In population based studies GTC most common Forsgren et al 1990 Institution based studies CPS +/- GTC most common Mariani et al 1993 Tonic, atonic, myoclonic and atypical absence seizures are also seen. Seizure types are age related GTC and CPS predominate at later ages

8 Seizure classification ILAE classification is not easily applicable to mentally retarded epileptic patients < 34% could classified by Mansford et al 1992 < 28% could classified by Mariani et al 1993

9 Tonic seizures

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11 Atonic seizures

12 Differential diagnosis 2/3 rd institutionalized patients with intellectual disability have stereotypical behavior e.g. head movements, rocking and jerking Berkson & Davenport 1962 Medication side effects e.g. tardive dyskinesia can mimic seizure Paul 1997

13 Morbidity Several factors have an impact on the caring of intellectually disabled individual Maladaptive behavior Severity of intellectual disability Presence of multiple disabilities Level of social support

14 Maladaptive behavior & psychiatric disorder Espie at al found people with double disability showed poor life skills than peers Aggression & self injurious behavior strongly associated with frequent seizures and antiepileptic polytherapy.

15 Morbidity of the Care-givers 108 children with epilepsy, presence of intellectual disability had a significant impact on caregivers Hoare 1993 Carers experience stress and prone to clinical anxiety & depression Espie et al (1998)

16 Physical morbidity Intellectually disabled have high incidence of vitamin D deficiency (Wageman et al 1998) Concomitant use of antiepileptic medication can be an additional factor Intellectually disabled with epilepsy have a much higher rate of fracture.

17 Mortality Patients with epilepsy have increased risk of mortality Patients with intellectual disability have increased risk of mortality The risk of mortality is even higher in epilepsy patients with intellectual disability

18 Seizures provoking factors Fever Infection Constipation Noncompliance with medications Medications side effects

19 Treatment: General principles Several factors, besides seizures, need special attention Therapy should not focus solely on seizure freedom. These patients already have limited quality of life that needs to be preserved and enhanced.

20 Cognitive Side effects Investigation/treatment hampered by lack of communication CNS side effects of antiepileptic drugs may be masked. Drowsiness, mood change and behavioral problems may represent toxicity Side effects may manifest as behavioral problem Devinsky 1995

21 Antiepileptic medications Drug compliance Cooperation difficulties, swallowing difficulty Drugs available as liquid, in soluble form, as powder or as granular may be useful Rectal suppository and IV formulation Caregivers are extremely important In mild MR drug dispensers & alarm watches

22 Worsening of Seizures Some AEDs may have paradoxical effect Can be due to overdose or specific effect Phenytoin encephalopathy can manifest as frequent seizures Iivanainen 1987 Carbamazepine can worsen symptomatic atypical absence Lerman 1986 GTC seizures Snead and Hosey, 1985

23 Worsening of Seizures Benzodiazepines can worsen tonic seizures in Lennox- Gastaut syndrome. Homan et al 1997 Vigabatrin can worsen absence, myoclonic, tonic and GTC seizures Lamictal may worsen severe myoclonic epilepsy of infancy Guerrini et al 1998 Many AEDs may cause enhanced aggressiveness & violence in MR patients Beran &Gibson, 1998

24 Treatment Alvarez (1989) suggested AED withdrawal after 2 yrs. N= 50 Recurrence of seizures 26 patients 52% 11 patients had recurrence during withdrawal 80% of discontinuation happened <3yrs.

25 Predictors of successful discontinuation History of few documented seizures No gross neurological abnormalities Non therapeutic levels at discontinuation Persistent normal EEG pre and post discontinuation

26 Surgical treatment An IQ< 70 was considered a relative contraindication for surgical treatment Engel 1993 If the seizure onset is focal from a brain lesion resective surgery should be considered irrespective of the IQ. In older patients the chances for multiple epileptogenic lesions is high Early intervention may prevent worsening

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28 Geriatric Epilepsy

29 Hauser WA. Epilepsia Age-Specific Incidence of Epilepsy by Gender in Rochester, Minnesota:

30 Incidence of unprovoked seizures and epilepsy in Iceland Incidence of all unprovoked seizures by age in Iceland from 1995 to 1999 DrElias Olafsson et al Lancet Neurol Oct;4(10):627-34

31 Epilepsy in the Elderly Epilepsy cases rise sharply after age 60 Incidence at age 50 years is ~ 28/100,000/yr Incidence at 60 years is 40/100,000/yr Incidence at 75 years is 139/100,000/yr

32 Demographics Different for younger people with epilepsy

33 Elderly (>65 years) Incidence of Alzheimer's 123/100,000 Incidence of Epilepsy 134/100,000 Olmsted County Data

34 Epilepsy in the Elderly: Incidence and Etiology

35 Factors Associated With an Altered Risk of Epilepsy Family history of seizures 2.5 Severe military head trauma 580 Severe civillian head trauma 25 Moderate head trauma 4 Mild head trauma Stroke 1.5 * 22 Viral encephalitis 16.2 Alzheimer's disease 10 Bacterial meningitis Multiple sclerosis Aseptic meningitis Alcohol 10.1 Heroin Marijuana No adverse exposure Adapted with permission from Hauser WA, Hesdorffer DC. Epilepsy Foundation of America Relative Altered Risk *Not statistically significant.

36 Epilepsy in the Elderly: Seizure Type Complex Partial 38% Generalized Tonic-Clonic 27% Simple Partial 14% Mixed 20% VA Co-op 2003 n=593

37 Epilepsy in the Elderly: Concurrent diseases Hypertension 64% Stroke 53% Cardiac Disease 49% Diabetes 27% History of Cancer 22% VA Co-op 2003 n=593

38 Epilepsy in the Elderly: Imaging Normal 18% CVA 44% Small vessel disease 40% Diffuse atrophy 35% Encephalomalacia 9% VA Co-op 2003 n=593

39 Epilepsy in the Elderly: EEG Normal 31% Epileptiform 39% Focal Slow 40% Generalized Slow 16% VA Co-op 2003 n=593

40 Stroke As A Cause Of Epilepsy Annual Incidence of Stroke (Williams, 2001) 750,000 in U.S. (1996) Seizures after Stroke Cooperative Study (Bladin, 2000) Prospective, 9-month follow-up, n=2021 Seizures in 8.9% 2.3% recurrent seizures

41 Table 1: Risk Factors for Developing Seizures Patients Patients with without seizures, seizures, n (%) n (%) Significanceª Type of stroke Ischemic 13 (7) 170 (93) Hemorrhagic 9 (25) 27 (75) 0.01 Location of lesion Cortical Subcortical 16 (17) 77 (83) 6 (4.7) 120 (95.3) 0.01 Size of lesion Large Small 14 (21.2) 52 (78.8) 8 (5.2) 145 (94.8) 0.01 ª Chi-square.

42 Table 2: Time Between Symptomatic Supratentorial Brain Infarct and First Seizure in 58 of 65 Patients with Postinfarct Epilepsy, Registered in the MECR (in seven times of stroke not certified). Seizure Delay Number Percentage of Patients <2 weeks 14 24% >2 weeks - <1 Year 22 38% >1 year - <2 years 11 19% >2 years 11 19%

43 Table 3: Infarct Types on CT in 38 Patients With Epileptic Seizures After Symptomatic Supratentorial Brain Infarction Infarct Type Number of Patients (%) Cortical infarct(s) only* 28 (73.7) Lacunar infarcts(s) only 6 (15.8) Cortical and lacunar infarct 2 (5.3) Cortical and striatocapsular infarct 1 (2.6) Cortical and watershed infarct 1 (2.6) * Six had two infarcts Three had two infarcts, one had seven infarcts

44 Seizures in Alzheimers Autopsy verified, n=81 10% had seizures Hauser, 1986

45 Epilepsy in the Elderly Epilepsy in the elderly is often misdiagnosed

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51 Delay In Diagnosis VA Co-op Subset (n=167), months to seek medical attention 1.7 years to correct diagnosis GTC: immediate diagnosis in 67% Less dramatic seizures often ignored Concomitant cardiac or cerebrovascular disease caused delays in diagnosis Spitz, et al

52 Diagnosis of Epilepsy: Elderly Compared to Younger People Higher percentage of partial seizures More extra-temporal onset complex partial seizures (missing classic auras) More prominent post-ictal symptoms Weaker historians EEG less helpful More concomitant illnesses

53 Some Diagnostic Dilemmas GTC vs. syncope Complex partial seizure vs. TIA Transient Global Amnesia

54 GTC Compared to Syncope GTC Syncope History of Cardiac Disease Common Common Positional Variable Orthostatic Warning Variable Pre-syncope Tongue biting Common Unlikely Complexion Normal Pale After Event Confused, sleepy Alert Movements Tonic-clonic Loss of tone, brief clonic movements Duration 1-2 minutes seconds to then post-ictal minutes Incontinence varies varies

55 Complex Partial Seizures Compared to TIA CPS TIA Hx of CV Disease Common Common Anatomic distribution Not Vascular Vascular Confusion, unresponsiveness Present Absent (may be aphasic) Frequency Can be frequent Rarely frequent Amnesia Common Absent Aura Common Absent Automatisms Common Absent

56 Treat or not to Treat The risk of recurrence of seizures is about 30-35% after the first unprovoked seizure The risk of recurrence is about 70% after second seizure Recurrence rate in elderly

57 Epilepsy in the Elderly: Pharmacokinetics and Drug Interactions

58 70% of new onset Epilepsy patients were first seen by nonneurologists

59 Determinants of Quality of Life in Patients with Epilepsy Relationship Between Seizure Frequency and Quality of Life QOLIE-89 Total Score n = 195 (r =.01, P =.93) Average Monthly Seizure Rate Gilliam F. Neurology. 2002;58(suppl 5):S9-S19. Reprinted with permission.

60 Determinants of Quality of Life in Patients with Epilepsy Relationship Between Adverse Events and Quality of Life QOLIE-89 Total Score n = 195 (partial correlation r =.061, P <.001) Adverse Event Profile Score Gilliam F. Neurology. 2002;58(suppl 5):S9-S19. Reprinted with permission.

61 Pharmacokinetic overview of classical AEDs PHT CBZ VPA PHB PMD ESX CZP Bioavailability >90% 75-85% >90% >90% >90% >90% >80% Protein binding 90% 75% 90% 45% <20% <10% 86% % Metabolism 95% >95% >96% <80% Metabolism site Liver Liver Liver Liver Liver Liver Liver T1/ Autoinduction no yes no no no no no

62 Are AED Pharmacokinetics and Drug Interactions in the Elderly Important Issues? Medication use is greatest in old age Older AEDs are frequently prescribed to elderly 1,2 AED efficacy and safety profiles differ from younger patients Pharmacokinetics change with age Greater risk of drug interactions 1. Lackner, Cloyd et al. Epilepsia. 1998;39: Nitz NM, Garrard J, et al, AES, 2000;41(suppl 7):215

63 Co-Medication Use in Elderly Nursing Home Residents on AEDs Drug Category Antidepressants Antipsychotics Benzodiazepines 12.7% 19% 22% Thyroid Supplements Antacids Antiepileptic Drugs Calcium Channel Blockers Warfarin Cimetidine 0 14% 8% 12% 7% 5.9% 2.5% Lackner, Cloyd et al, Epilepsia 39: , Maintenance Medication Use by Elderly Nursing Home Residents + AED AED 6 meds 5 meds % of Antiepileptic Drug Recipients

64 AED Efficacy and Safety in the Elderly Elderly Appear more responsive to AED therapy at lower concentrations Have an increased risk of adverse reactions

65 Physiological Changes of Aging Affecting AED Pharmacokinetics in GI anatomy variable absorption Serum albumin altered protein binding Hepatic blood flow Liver Mass Oxidative reactions ( 1%/yr 40 yrs) or conjugation reactions? Induction of microsomal enzymes? Glomerular filtration ( 1%/yr 40 yrs) Disease may exacerbate physiologic changes However, there are few AED pharmacokinetic studies in the elderly, esp. oldest-old ( 85)

66 AED Pharmacokinetics in the Elderly: Protein Binding Several AEDs are highly bound to serum proteins, primarily albumin - Carbamazepine 75-85%* - Valproate 80-95% Phenytoin 90% - Tiagabine 96% * CBZ binds to both albumin and alpha 1 acid glycoprotein (AAG) Changes in protein binding cause misleading measurement of total concentration of highly bound AEDs Cloyd, 1998.

67 Use of AED ER Formulations in the Elderly Elderly are at greater risk for noncompliance due to # of medications and cognitive impairment Elderly may be more susceptible Cmax-related side effects, particularly from rapidly absorbed AEDs ER formulations may Enhance compliance by reducing dosing frequency Improve therapeutic outcomes Decrease peak-related side effects Improved efficacy with higher blood levels Decrease nursing medication administration time

68 Isoenzyme-Mediated AED Metabolism and Drug Interactions AED Substrates Inhibitors Inducers CYP 1A2 CYP 2C9 CYP 2C19 CYP 3A4* UGT CBZ (minor) PHT Diazepam PB PHT (minor) VPA (minor) Cimetidine Ciprofloxacin Enoxacin Fluvoxamine Tacrine Ticlopidine Cigarette smoke Omeprazole Charbroiled meats Amiodarone Cimetidine Felbamate Fluconazole Fluoxetine Fluvastatin Isoniazid Losartan Ticlopidine CBZ Rifampin St. John s wort Fluvoxamine OXC, MHD (weak) Omeprazole Ticlopidine TPM Dexamethasone Phenytoin Phenobarbital Rifampin Rifapentine St. John s wort CBZ epoxidation Clonazepam Diazepam Felbamate Ethosuximide Midazolam Tiagabine ZNS Azole antifungals (eg, ketoconazole) Cimetidine Erythromycin Clarithromycin Diltiazem HIV Protease Inhibitor Fluoxetine Grapefruit juice Nefazodone Sertraline (weak) CBZ PHT PB Rifampin Rifapentine Rifabutin St. John s wort Lorazepam Lamotrigine MHD VPA VPA CBZ LMT PB PHT Rifampin OCs (LMT) * CYP3A4: catalyzes biotransformation of 50% of all drug undergoing metabolism

69 Relationship of PHT Half-Life with Age Age (years Cloyd et al, 2004

70 Phenytoin-Simulated Dosing Requirements in Elderly vs Younger Adults Phenytoin Concentration (mg/l) Differences in PHT Content: Capsules 92% Infatabs 100% Suspension 100% Time to SS = 3-5 wk Daily Dose (mg/kg) as PHT Acid 8 Elderly (60-79 y) 1 Vmax = 5.5 mg/kg/d Km = 5.8 mg/l Adults (19-64 y) 2 Vmax = 8.45 mg/kg/d Km = 6.25 mg/l Bauer and Blouin. Clin Pharmacol Ther. 1982;31: Cloyd et al. Epilepsy International Symposium Vancouver, Canada.

71 Effect of Age on Total Plasma Valproate Concentrations 6 young, 6 elderly volunteers 400 mg dose Total Plasma VPA (Ìmol/L) Total Plasma Valproate Concentrations Free Fraction 6% 11% Time (h) Perucca et al. Br J Clin Pharmacol. 1984;17:

72 Effect of Age on Unbound VPA Concentrations Free Plasma VPA (Ìmol/L) Unbound Plasma Valproate Concentrations Free Fraction 6% 11% Time (h) Perucca et al. Br J Clin Pharmacol. 1984;17:

73 Pharmacokinetics of Newer AEDs Drug Absorption Binding Elimination T 1/2 (hr) Interactions* GBP 60% 0% 100% renal 5-9 No LTG 100% 55% 100% hepatic Uni-D LVT ~100% <10% 66% renal 4-8 No OXC/MHD 100% 40% 100% hepatic 5-11 Bi-D PGB 90% 0% 100% renal 5-7 No TGB ~100% 96% 100% hepatic 5-13 Yes TPM 80% 15% 30%-55% renal Bi-D ZNS 80%-100% 40%-60% 50%-70% hepatic Uni-D In noninduced adult; Saturable; Binding, elimination, and t 1/2 refer to MHD; *Bi-D=bidirectional; Uni-D=unidirectional. Adapted from Cloyd JC, Remmel RP. Pharmacotherapy. 2000;20:139S-151S.

74 Effect of CBZ on Serum Simvastastin and Simvastatin Acid Concentrations Ucar et al, EJCP, 2004

75 Effect of Grapefruit Juice on Drug Metabolism

76 Inhibition of CYP 3A4 by Grapefruit Juice: Effect on Carbamazepine Serum Levels CBZ + Grapefruit juice CBZ CBZ Concentration (mg/l) Time (hours) Garg et al. Clin Pharmacol Ther. 1998;64:

77 Potent inducer of CYP 3A enzymes

78 Herbs and Epilepsy Herbs may increase the risk for seizures: intrinsic proconvulsant properties contamination by heavy metals effects on the cytochrome P450 enzymes and P- glycoproteins, herb drug interactions

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80 Epilepsy Treatment in the Elderly Monotherapy is possible for 90%+ of patients. Typical nursing home patient is on 6-8 medications. Choose AEDs with minimal interactions e.g. levetiracetam, pregabalin and gabapentin Titrate slowly Avoid older AEDs with strong induction effects (phenytoin, phenobarbital, and carbamazepine) Avoid newer AEDs with established adverse cognitive effects (topiramate and zonisamide)

81 Topiramate and Zonisamide 94% of patients experienced cognitive viscosity with either drug as an adjunctive agent* 63% of the patients were unaware of the effect* Lee S, Sziklas V, Andermann, et al. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia, Vol 44, No 3, 2003:

82 Oxcarbazepine and Tiagabine Oxcarbazepine can result in hyponatremia much more commonly in elderly Tiagabine has been associated with encephalopathy

83 Older AEDs and the Elderly Inducing drugs: phenytoin, carbamazepine and phenobarbital result in consequences Behavioral Cognitive Valproate - weight gain, risk of encephalopathy. Can be used, but carefully. Phenobarbitol can have significant cognitive slowing, depression, or other behavioral consequences

84 80% of 21,435 pts. received phenobarbital or phenytoin. Most patients were taking phenytoin 18.9% of patients with previously diagnosed epilepsy 9.4% of patients with newly diagnosed epilepsy received phenobarbital White veterans Patients receiving neurology consultation were half as likely to receive phenytoin monotherapy. J Am Geriatr Soc Mar;52(3):

85 Epilepsy in long term care patients Not rare Demographics different than normal intelligence people Often misdiagnosed Can be treated with monotherapy Side effects are more common Use new seizure medications

86 Questions & Answers

87 Thank you for your attention.